Difficult business requires investment in the right infrastructure and skilled people, as well as developing the right processes for efficient and profitable manufacturing.

At BioProcessUK’s recent meeting in Liverpool, Steve Bates, CEO of the BioIndustry Association (BIA), the trade body for bioscience companies in the U.K., explained how valuable biologics and vaccine manufacturing is to the country, by stating: “The U.K. medicines manufacturing industry, which includes biologics is one of our leading manufacturing sectors; worth £22 billion in exports, generating a trade surplus of £4.9 billion in 2012, and Gross Value Added per head of £149 thousand, significantly higher than any other industry.”

However, manufacturing biologics and advanced therapies is not an easy business as it requires investment in the right infrastructure and skilled people, as well as developing the right processes for efficient and profitable manufacturing.

Eli Lilly is just one of the major pharmaceutical companies that has invested in the U.K. and has built considerable manufacturing expertise in Speke near Liverpool. Peter Whyment, a consultant scientist at Eli Lilly with many years’ scale-up experience, described the issues facing process development scientists and showed a table that Lilly uses to pinpoint where biologic product-related impurities could be introduced and where they can be controlled.

“Down time and clunky processes are your enemy in biologics manufacturing,” commented Whyment.” His advice on scaleup was simple: “Go up in steps of no more that 10x scaleup at a time, if the models are available. Build it layer by layer like an onion with lab to pilot and then manufacture.”

He cited an example of a protein refolding reaction in which a 20 L beaker was used as a model for 5,600 L mixing tank, a 300 fold scaleup. In the mixing tank, a foam was produced, which was not seen in the beaker model, a problem which was remedied by putting a tube down the side of the tank before going into the 8,000 L manufacturing scale tank. Whyment concluded: “Often if you go for a 300-fold scaleup it will rarely work out well, as this example shows the poor yields of the final product caused by the foam were not been seen in the beaker model. He added: “GMP manufacturing is still quite an unpredictable business.”

Whyment detailed how process expertise is transferred and developed at Lilly by describing their training program whereby new staff have to work in process development, product support, and tech transfer departments because he stated: “this helps young scientists that are more lab research minded to understand what to do for the best outcomes and to understand the stuff that simply won’t fly in scale-up.”

The Right Chemistry

Among the advanced therapies showcased at BioProcessUK, where getting the manufacturing right is key to drug safety and profitability were antibody drug conjugates (ADCs). Dave Simpson, Ph.D., CEO of ADC development biotech, Glythera, noted: “In 2014, the first patient in the U.K. was treated with the ADC, Adcetris for non-Hodgkin’s’ lymphoma. After 12 weeks his 76 tumors were gone and he was disease free so ADCs are game-changing drugs. So much so that in 2014 there were 40 distinct ADCs in clinical trials and by July 2014 there were 219 clinical trials with several large pharmas signing up to gain access to novel linkers and toxin payloads.”

However, because ADCs consist of an antibody, a linker, and a highly potent toxic drug, manufacturing them can be complicated. Dr. Simpson explained: “Originally the challenge with ADCs was to bolt on something that was sufficiently toxic. Then when we got that right, the linker stability became a problem and it meant the toxic payload was not always delivered to the right target.”

To get around this stability challenge, Dr. Simpson discussed a cysteine-specific conjugation linker called Permalink™, developed by Glythera. He presented data on trastuzumab/MMAE (monomethyl auristatin E) based ADCs that showed the addition of Permalink generated stable ADCs and resulted in enhanced anticancer activity in cell-based assays, as well as a xenograft model.

Even when the antibody, linker, drug combination is stable, manufacturing ADCs can bring considerable bioprocessing challenges. According to Dr. Simpson, “Today, the linkers and molecules are already out there, so ‘there is no secret ingredient’ and our challenges today are bioprocess ones as manufacturing brings in a chemistry arm to the process.”

Jon Dempsey, Ph.D., head of process introduction at contract development and manufacturing company, Piramal Healthcare, agreed, stating: “With ADCs, as the payloads have become more toxic and potent they have become more difficult to manufacture. The problem is trying to marry the chemical and biochemical needs of the final molecule. Sometimes, for example, adding a linker to the purified antibody causes aggregation that requires chromatographic purification and reformulation with an excipient. This solves the problem but adds in extra costs. Additionally, with ADCs often the toxic drug part is in a solvent that has to be removed but the difficulty is if this is done in single-use plastic purification platforms, there can be leeching from the plastics.”

Dr. Dempsey detailed how manufacturing ADCs requires a full DoE (Design of Experiments), which includes testing Drug Antibody Ratio (DAR), reducing agents and temperature of conjugation. According to Dr. Dempsey finding the correct DAR is vital to maximize loading of tangential flow filtration (TFF) filters and also adding too much of the drug can lead to disposal problems. “Developing the correct conjugation protocol for ADCs is critical to getting the balance of efficacy, toxicity, and cost-effective manufacturing. When this is achieved routinely, then ADCs will become a much more accepted class of medicine.”

Beyond Small-Scale T-Flasks

Cell therapies were discussed as another class of therapy where developing robust manufacturing processes is crucial for decreasing the cost of good and delivering efficacious products. Stephen Ward, Ph.D., COO of the Cell Therapy Catapult, which assists in developing and commercializing cell therapies, said: “The U.K. has a reasonable slice of the cell therapy market because the industry is maturing here. It is no longer about post-docs scraping cells from T-flasks into 6 well plates, now it has some industrial manufacturing capability behind it. To continue this, we need to call on all the expertise from vaccine and biologics manufacturing and apply some of that to cell therapy to enable the production of these expensive therapies to be profitable.”

One company that is demonstrating this expertise is ReNeuron, a firm developing allogeneic cell therapies (CTX), including a neural stem cell line to treat a number of indications, with the furthest advanced being the use of CTX to address the damage caused post-stroke. According to Sharon Grimster at ReNeuron in 2011 in their PISCES (Pilot Investigation of Stem Cells in Stroke) study, 20 million cells/vial were produced and the cells had to be used within days to be effective. Since then the firm has developed a cryopreserved formulation that has a shelf life of three months, as well as a robust manufacturing process by collaborating with companies and academic partners including the Cell Therapy Catapult, Loughborough University, PharmaCell, and Roslin Cells. Grimster stated: “We began collaborating with different partners via the Cell Therapy Catapult in 2013 to use QBD (Quality by Design) principles to deliver a process that would establish the CQAs (Critical Quality Attributes), which would then further enable the automation of our scaled-up process.”

In 2015, ReNeuron’s manufacturing is relocating to Wales where at the Pencoed ATMP facility the firm will use manufacturing-scale automation to produce larger batches of cells in T flasks. Grimster commented: “This work has required a significant amount of process optimization. Next year when we’re validating our process in the facility in Wales we will have security over the supply chain and this is a key asset. Going forward automation and cryopreservation will make this process cost-effective and means our cell therapy will be a good commercial product.”

Grimster added: “twenty two years ago when I was scaling up EPO production I used the same type of robot we’re now using to automate large scale production of our cell therapy, which shows how some of the processes we’ve learned from biologics manufacturing can be transferable to cell therapy production.”

Grimster concluded: “Getting to this stage has been a collaborative effort bringing together all the best cell therapy teams in the U.K. The MHRA has also been very supportive as they are of cell therapy as a whole so our next steps are commercialization and putting in place a global distribution strategy for our cell therapy.”

To ensure the U.K is concentrating its efforts on improving manufacturing of biologics and advanced therapies, a number of initiatives are being put in place. These include the Medicines Manufacturing Industry Partnership (MMIP), which was established in September 2014 by the Association of the British Pharmaceutical Industry (ABPI) and the BIA. Many pharma and biotech organizations are involved in the partnership including: Actavis, AstraZeneca, Eisai, FUJIFILM Diosynth Biotechnologies, GlaxoSmithKline, Oxford BioMedica, and Pfizer. Additionally, Cell Therapy Catapult just announced that it will build a £55 million cell therapy manufacturing center in Stevenage, U.K.

Speakers at BioProcessUK agreed that manufacturing of biologics and advanced therapies should continue to receive government investment if the U.K. is to play an active role in the global biopharm market. Dr Ward echoed these sentiments, when he stated: “For manufacturing effectively, you need the holy trinity of discovery science, manufacturing science and GMP manufacturing if you lose one of these all the other parts will go in the U.K., which is why we have to continue bolster our GMP manufacturing capabilities here.”